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Abstract

Background

As a quality improvement metric, the US Veterans Health Administration (VHA) monitors
the proportion of patients with alcohol use disorders (AUD) who receive FDA approved
medications for alcohol dependence (naltrexone, acamprosate, and disulfiram). Evidence
supporting the off-label use of the antiepileptic medication topiramate to treat alcohol
dependence may be as strong as these approved medications. However, little is known
about the extent to which topiramate is used in clinical practice. The goal of this
study was to describe and examine the overall use, facility-level variation in use,
and patient -level predictors of topiramate prescription for patients with AUD in
the VHA.

Methods

Using national VHA administrative data in a retrospective cohort study, we examined
time trends in topiramate use from fiscal years (FY) 2009–2012, and predictors of
topiramate prescription in 375,777 patients identified with AUD (ICD-9-CM codes 303.9x
or 305.0x) treated in 141 VHA facilities in FY 2011.

Results

Among VHA patients with AUD, rates of topiramate prescription have increased from
0.99% in FY 2009 to 1.95% in FY 2012, although substantial variation across facilities
exists. Predictors of topiramate prescription were female sex, young age, alcohol
dependence diagnoses, engagement in both mental health and addiction specialty care,
and psychiatric comorbidity.

Conclusions

Veterans Health Administration facilities are monitored regarding the extent to which
patients with AUD are receiving FDA-approved pharmacotherapy. Not including topiramate
in the metric, which is prescribed more often than acamprosate and disulfiram combined,
may underestimate the extent to which VHA patients at specific facilities and overall
are receiving pharmacotherapy for AUD.

Keywords:

Background

Four medications have been approved by the US Food and Drug Administration (FDA) for
the treatment of alcohol dependence, including naltrexone (both oral and injectable
extended release), acamprosate, and disulfiram [1]. Naltrexone is an opioid antagonist that reduces the reward properties of and cravings
for alcohol [2]. Acamprosate reduces cravings and has been found to be efficacious in maintaining,
but perhaps not producing, abstinence [3]. While disulfiram may be more familiar to clinicians than naltrexone or acamprosate,
some clinical practice guidelines do not recommend disulfiram as a first-line pharmacological
treatment because of significant toxicity risks and limited evidence of effectiveness
[4].

Utilization rates for the four FDA-approved medications are generally low [1]. Of the approximately 19 million patients meeting criteria for alcohol dependence
in the United States, less than 150,000 are treated with FDA-approved pharmacotherapy
[5,6]. In 2009, among patients of the US Veterans Health Administration (VHA), the largest
health-care system in the United States, 4.7% of veterans with diagnosed alcohol dependence
(3.4% with any alcohol use disorder [AUD]) filled at least one prescription for naltrexone,
acamprosate, or disulfiram [1]. As with other classes of psychiatric medications, such as antidepressants, each
of the medications for AUD has particular strengths, contraindications, and side effects;
therefore, a specific patient may benefit more from one medication compared with another.
Ideally, patients should have access to as many efficacious medications for AUD as
possible so they can work with their health-care providers to find the agent that
maximizes benefits while minimizing side effects.

Several medications, other than the four approved medications for alcohol dependence,
have shown promise in reducing alcohol consumption. Perhaps the most impressive evidence
exists for the antiepileptic medication topiramate, shown to reduce alcohol consumption
[7-9] with clinical effect sizes that are at least as large as naltrexone and acamprosate
[10]. Johnson and colleagues found that 300 mg per day of topiramate reduced heavy drinking
days 8.5% more than a placebo [8]. However, topiramate was also associated with certain side effects compared with
placebo, including paresthesia, taste perversion, anorexia, and difficulty with concentration.
A review of many studies of topiramate in the treatment of psychiatric disorders concluded
that it is generally well-tolerated with the most common serious adverse events being
paresthesia/numbness (12.9%), nausea/vomiting (6.2%), cognitive impairment (5.4%),
headache (5.0%), and dizziness (5.0) [11].

Although not well understood, topiramate is thought to reduce craving for alcohol
by targeting the glutamate brain pathways [12] and inhibiting dopamine release [9]. Interestingly, topiramate has also been found to be effective for other off-label
uses, such as amelioration of obesity [13], eating disorders [14], and migraine headaches [15]. Of particular relevance, evidence suggests that topiramate has mood stabilizing
properties [16] and is efficacious for treating certain psychiatric disorders, including bipolar
disorder [11], borderline personality disorder [16], and post-traumatic stress disorder [17]. Alcohol dependence is often comorbid with these disorders; therefore, topiramate
may be viewed by clinicians as a way to address multiple problems with one medication.

Although the utilization of FDA-approved pharmacotherapy for alcohol dependence in
the VHA is known to be low and variable [18], nothing is currently known about the overall use of topiramate for alcohol dependence.
Currently, VHA facilities are monitored regarding the extent to which patients with
AUDs are receiving FDA-approved medications [19]. However, topiramate, which appears to be at least as effective as naltrexone, acamprosate,
and disulfiram, is not included in current quality improvement metrics in the VHA
or elsewhere [20]. Therefore, the extent to which VHA patients, at specific facilities or overall,
are utilizing pharmacotherapy for AUDs may be underestimated. The goal of this study
was to examine overall (and facility-level) prescription rates of topiramate for patients
diagnosed with AUDs and time trends in the receipt of topiramate, as well as which
patient characteristics are associated with greater likelihood of receipt of topiramate
through prescription.

Methods

Calculating receipt of topiramate across four years

For each fiscal year (FY) (from October 1 through September 30, 2009–2012), we used
the VHA National Patient Care Database (NPCD) to identify all veteran patients that
had an AUD diagnosis (alcohol abuse or alcohol dependence, ICD-9-CM codes 303.9x or
305.0x) recorded in any outpatient or inpatient encounter during those years. Even
though topiramate has primarily been studied in patients with alcohol dependence diagnoses,
we included patients with alcohol abuse diagnoses due to the unreliability of this
diagnostic distinction in clinical data and for consistency with the VHA quality improvement
metrics, and because the abuse/dependence distinction has been eliminated in the revised
Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (http://www.dsm5.orgwebcite). We then used the VHA Decision Support System (DSS) inpatient and outpatient pharmacy
benefits datasets to determine the number of patients with AUD who filled a prescription
for topiramate (defined as at least one VHA pharmacy record for topiramate) during
the same year as their AUD diagnosis (either a new or ongoing diagnosis). From these
data, we were able to calculate the annual rates of topiramate prescription among
patient with AUD within the 141 VHA facilities nationwide.

Patient characteristics predicting topiramate prescription

Using only the FY 2011 cohort—the most recent year for which all relevant data were
available—we examined the patient-level predictors of topiramate prescription. From
the NPCD we obtained data regarding gender, age (categorized as age <30, 30–55, >55),
alcohol diagnosis (categorized as having an alcohol dependence diagnosis at any time
during the year versus only an alcohol abuse diagnosis), receipt of mental health
and/or addiction specialty care (categorized as “none,” “mental health,” “addiction,”
and “both mental health and addiction”), and psychiatric comorbidities (categorized
as “none,” “bipolar,” “depression,” “PTSD,” “PTSD and depression,” “schizophrenia,”
and any other combination, classified as “other/multiple”) to determine their relationship
with any topiramate prescription. The classification of psychiatric comorbidities
into one of the seven mutually exclusive categories was based on previous research
of topiramate for treating psychiatric illness [11] and on meeting a minimal percentage breakdown (>2% of total sample with particular
psychiatric diagnosis required) into one of the mutually exclusive bins.

Analytic plan

To describe and explore variability in facility-level rates of topiramate prescription,
we calculated the rate of topiramate prescription (number of AUD patients who had
at least one pharmacy record for topiramate divided by the total number of AUD patients
in the facility) in FY 2011 for each of the 141 VHA facilities. All analyses predicting
topiramate utilization at the patient level (0 = no, 1 = yes) were performed using
generalized logistic mixed-effects models with a random effect for facility to account
for the clustering of patients. We also conducted sensitivity analyses that explored
the effect that the inclusion of patients diagnosed with migraine or seizure disorders
may have had on our results. These sensitivity analyses included crosstabs of the
number in our sample with either migraine or seizure disorders, the correlation between
facility prescription rates of topiramate and FDA-approved medications for AUD (naltrexone,
acamprosate, and/or disulfiram), and additional mixed-effects regression models that
excluded patients diagnosed with migraine or seizure disorders. The mixed-effects
regression models were conducted using the GLIMMIX function within the SAS statistical
software (version 9.2), and graphics were produced with the ggplot2 package within
the R statistical software (version 14.2). The VA Palo Alto Health Care System’s research
office and Stanford University’s Human Research Protection Program approved this project.

Results

Table 1 presents data on the percent of patients with AUD who received topiramate from FY
2009 through 2012. Approximately 10% of patients prescribed topiramate also received
one of the other FDA-approved medications for AUD during the same fiscal year. In
FY 2009, nearly 1% (n = 3736) of the 372,817 patients with an AUD filled a prescription
for topiramate. This rate increased to 1.45% (n = 5270) in FY 2010 among 357,467 patients
with AUD. In FY 2011, 1.45% (n = 5454) of all veterans with AUD (N = 375,777) filled
a VHA pharmacy prescription for topiramate. In FY 2012, 1.95% (n = 7427) of all veterans
with AUD (N = 381,815) filled a VHA pharmacy prescription for topiramate. Within the
141 VHA facilities in FY 12, the overall proportion of patients who received topiramate
ranged from 0% to 6.5% (mean, 2.03%; median, 1.69%) with seven sites prescribing topiramate
to more than 2% of patients with AUD. When restricting the analyses to patients who
had contact with VHA addiction specialty care within the year, the facility-level
proportions of patients who received topiramate ranged from 0% to 13.4% (mean, 2.97%;
median, 2.47%) with 16 sites prescribing topiramate to more than 5% of patients with
AUD.

Table 1.Patients who received topiramate for alcohol use disorders in the Veterans Health
Administration, 2009–2012

In the unadjusted single-predictor models, veteran patients with an AUD were more
likely to fill a prescription for topiramate in FY 2011 if they were female, younger,
had alcohol dependence, were involved in both mental health and addiction specialty
care, and had a psychiatric comorbidity (Table 2). These results remained consistent in the adjusted multi-predictor analyses (Table 3). Specifically, patients were more likely to be prescribed topiramate if they were
female (OR = 2.50; 95% confidence interval (CI), 2.31, 2.71), were between 30–55 years
old compared with >55 (OR = 1.66; 95% CI, 1.56, 1.76), had alcohol dependence versus
abuse (OR = 1.15; 95% CI, 1.08, 1.22), were involved in both mental health and addiction
specialty care (OR = 3.75; 95% CI, 3.24, 4.43), and had a psychiatric comorbidity
(depending on specific psychiatric diagnosis, estimates ranged from OR = 1.74; 95%
CI, 1.43, 2.11 for schizophrenia to OR = 4.497; 95% CI, 4.07, 4.96 for other multiple
psychiatric diagnoses). Figure 1 displays the facility prescription rates of topiramate by receipt of specialty care.

Figure 1.Percentage of patients in 141 facilities receiving topiramate in FY 2011 by receipt
of specialty care. Displayed is the variability in facility level percentage of patients prescribed
topiramate by specialty care services. The 141 VA facilities are ordered from smallest
to largest percentage and the size of each point represents the number of patients
within each respective specialty care service.

Table 2.Predictors of topiramate prescription and receipt of specialty care for alcohol use
disorders in the Veterans Health Administration, fiscal year 2011

Table 3.Multipredictor model predicting receipt of topiramate for alcohol use disorders in
the Veterans Health Administration, fiscal year 2011

As topiramate can be prescribed for disorders unrelated to alcohol use, we also conducted
a sensitivity analysis that explored the effect that the inclusion of patients diagnosed
with migraine or seizure disorders may have had on our results. First, we tabulated
the number in our sample with either migraine or seizure disorders (Table 4). As can be seen, 22.7% (n = 1239) of patients with an AUD and a prescription for
topiramate also had a migraine or seizure disorder diagnosis. In addition, we determined
which patients in our sample had contraindications for naltrexone, specifically acute
hepatitis or a prescription of opioid pain medication. We found that, among those
with a prescription for topiramate, 58% have contraindications for naltrexone, making
it more plausible that the topiramate was being used to treat the AUD. Further, we
examined the correlation between facility prescription rates of topiramate and FDA-approved
medications for AUD (naltrexone, acamprosate, and/or disulfiram) and found a modest
relationship (r < 0.20). Lastly, we reran the mixed-effects regression models analyses
above excluding patients diagnosed with migraine or seizure disorders. The results
of our models were virtually unchanged (i.e., some coefficients differed only at the
third decimal place, but findings were unchanged).

Also, we conducted analyses to compare the number of patients with AUD who were prescribed
topiramate with the number who were prescribed the FDA-approved medications in FY
2012. We determined that the 7427 patients receiving topiramate in FY 2012 was more
than the number of patients receiving acamprosate (n = 1662), injectable naltrexone
(n = 498), or disulfiram (n = 3455) but not as many as those receiving oral naltrexone
(n = 9646) in patients with AUD. Figure 2 displays the facility prescription rates of topiramate and FDA-approved medications
for AUD. Those facilities in the middle to upper-left quadrant of the figure (i.e.,
higher topiramate prescriptions and lower FDA-approved medication prescriptions) are
those facilities likely to be penalized and receive lower performance ratings.

Figure 2.Facility prescription rates of topiramate and FDA-approved medications for alcohol
use disorders. Displayed are the facility prescription rates of topiramate on the y-axis and FDA-approved medications for AUD on the x-axis.

Discussion

Although evidence supports the efficacy of topiramate for alcohol dependence [7-9,21-23], system monitoring metrics and quality measures of pharmacotherapy for AUD used within
VHA [19] and developed elsewhere [24] only include FDA-approved medications (naltrexone, acamprosate, and disulfiram).
This may not only underestimate actual overall patient utilization of pharmacotherapy
for AUD but also unnecessarily penalize those facilities with higher rates of topiramate
utilization.

We found that 1.95% of the nearly 400,000 patients treated in VHA facilities with
a diagnosis of AUD were prescribed topiramate—more than acamprosate, injectable naltrexone,
and disulfiram combined. Therefore, by not including topiramate in monitoring metrics,
patient prescription of pharmacotherapy for AUD may be underestimated by as much as
40% in the VHA. It is worth noting that only about 10% of patients prescribed topiramate
also were prescribed one of the other medications for AUD during the same fiscal year,
meaning that the possible undercount is quite substantial. That said, the underestimation
by 40% is the upper bound estimate due to limitations of the administrative data,
which did not permit us to determine what topiramate was filled for specifically (e.g.,
prescription for something other than AUD).

Relatedly, those facilities with higher rates of topiramate prescriptions (versus
FDA-approved pharmacotherapy) may falsely appear to have lower rates of pharmacotherapy
use for AUD. This finding is strengthened by the fact that we found a modest relationship
between facility prescription rates of topiramate and FDA-approved medications for
AUD. The consequence of this finding is that some VHA facilities with higher rates
of topiramate prescription for AUD may unjustifiably end up with lower AUD pharmacotherapy
performance ratings than they would if topiramate was included in the specifications
of these metrics.

At what point does a therapy become “evidence-based?” Currently, more than 10 studies
(four of which were randomized controlled trials [RCTs]) have been conducted examining
the efficacy of topiramate for alcohol dependence. A recent meta-analysis pooled the
results of three placebo-controlled trials and reported that topiramate was more efficacious
than placebo in terms of reducing the percent of heavy drinking days (23.2%; 95% CI,
15.7, 34.4) as well as increasing the number of abstinent days (mean difference, 2.9 days;
95% CI, 2.5, 3.3). The combined results of two other trials indicated that topiramate
is also more efficacious than naltrexone [7]. Studies published since this meta-analysis provide further support for the efficacy
of topiramate. One recent RCT of topiramate found those in the group with psychotherapy
plus low-dose topiramate fared better at post-test and four-month follow-up than those
allocated to psychotherapy alone (lower relapse rate in the topiramate group [66.7%]
compared with psychotherapy alone [85.5%]) [25]. The strength of the evidence in support of topiramate for the treatment of alcohol
dependence is at least on par with naltrexone and acamprosate and is stronger than
that for disulfiram. However, because topiramate is now off-patent, it is extremely
unlikely FDA approval will be sought for the treatment of alcohol dependence or any
other new indications; a pharmaceutical company would be unlikely to seek a new indication
for a medication through the costly FDA approval process if that medication is off-patent
and not proprietary. The first quality metrics in this domain within the VHA and elsewhere
[20] included only FDA-approved medications, even ones with poor evidence (i.e., disulfiram),
perhaps because this strategy had high face validity and avoided more complicated
judgments about which medications have sufficient supporting evidence. However, excluding
medications with strong evidence but no FDA approval from quality metrics is short-sighted.
Therefore, we encourage the inclusion of topiramate in related quality metrics and
in quality improvement efforts intended to increase the active consideration of medications
in the treatment of alcohol dependence.

Patient-level predictors

Several patient characteristics were associated with greater likelihood of receipt
of topiramate. Female patients with AUD were more likely than male patients to receive
a prescription for topiramate (5.2% compared with 1.3%). This result is not unique
to topiramate, as women, compared with men, are generally more likely to receive the
other medications for alcohol dependence as well as specialty addiction treatment
[1,26]. This association may be due to unobserved factors, such as women having greater
likelihood of psychiatric diagnoses and treatment-seeking behavior compared with men
[1].

Patients between age 30–55 were most likely (compared with those >55) to receive a
prescription for topiramate. These results were similar to Harris et al's study of
FDA-approved pharmacotherapy for AUD and may be related to older patients being less
likely to receive any addiction treatment, including pharmacotherapy, due to cohort
norms and stigmatization around treatment for alcohol dependence [1]. Another possible explanation for older patients receiving fewer prescriptions is
that they have more medical comorbidities and, therefore, may be taking other medications
that may be contraindicated for topiramate.

The rate of topiramate prescription was higher for patients diagnosed with alcohol
dependence than for those diagnosed with alcohol abuse. This finding was expected
and congruent with receipt patterns for the FDA-approved medications for alcohol dependence.
Topiramate prescription rates were also higher for patients who received care in both
VHA substance-use disorder and mental-health specialty treatment settings in the same
year. Further, patients with psychiatric comorbidities were much more likely to have
a prescription for topiramate (83% of patients with a prescription for topiramate
had at least one psychiatric comorbidity) (Table 2). Topiramate has mood stabilizing properties [16] and is efficacious for treating several psychiatric disorders (bipolar disorder [11], borderline personality disorder [16], and post-traumatic stress disorder [17]). As AUD is often comorbid with psychiatric disorders, topiramate may be viewed by
providers as a way to address multiple disorders with one medication.

Limitations

This study has several limitations, including a cross-sectional observational study
design that was limited to patients treated in VHA facilities, which limits causal
interpretation of findings and may not generalize to utilization patterns in other
health-care systems. Another limitation is that persistence of treatment with topiramate
was not examined, which may differ from our findings solely based on filling at least
one prescription for topiramate; we cannot determine, for instance, whether a patient
actually took the medication or whether there was treatment response or ill effect.
In addition, there were several unmeasured variables, such as treatment motivation
or the presence of other indications for topiramate, which may better explain the
reported associations. Finally, the data used in this study did not permit us to determine
if topiramate was specifically prescribed for AUD. In some cases, it may have been
prescribed for some other common indications (e.g., migraine or seizure disorder),
although 78% of the prescriptions for topiramate cannot be explained by these common
uses. Further, we conducted several sensitivity analyses that accounted for several
of these common indications and the results remained virtually unchanged.

Conclusions

Veterans Health Administration facilities are monitored regarding the extent to which
patients with AUD are receiving FDA-approved pharmacotherapy. Approximately 2% of
the nearly 400,000 VHA patients with AUD were prescribed topiramate, and there was
substantial facility-level variation in use. Several patient characteristics were
associated with greater likelihood of topiramate prescription, including being female,
younger age, diagnosis of alcohol dependence (versus alcohol abuse), treatment in
both mental health and addiction specialty care, and having a psychiatric comorbidity.
Not including topiramate in the quality improvement metrics appears to underestimate
the extent to which VHA patients, at specific facilities and overall, are being prescribed
pharmacotherapy for AUDs. We believe that the evidence is sufficient to consider topiramate
an evidenced-based treatment for alcohol dependence. Therefore topiramate should be
included in related quality measures and system monitoring metrics in VHA and elsewhere.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

AD participated in the study design, performed the statistical analysis, and helped
to draft the manuscript. AG participated in its coordination and helped to draft the
manuscript. AL participated in its coordination and helped to draft the manuscript.
AH conceived of the study, participated in its design and coordination, and helped
to draft the manuscript. All authors read and approved the final manuscript.

Acknowledgments

This study was completed in part with support from the VA Substance Use Disorder QUERI
and the VA Office of Academic Affiliations. The views expressed are those of the authors
and not those of the Department of Veterans Affairs.

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